Mutations in the activating enzymes catalyzing the 25-hydroxylation and subsequent 1α-hydroxylation of vitamin D, and mutations in the vitamin D receptor (VDR) interfere with signaling and can cause diseases characterized by hypocalcemia, secondary hyperparathyroidism, and severe early-onset rickets in infancy. By contrast, mutations in 24-hydroxylase that inactivates 25(OH)D and 1,25(OH)2D can cause both severe neonatal hypercalcemia and a less severe adult hypercalcemic syndrome. Mutations in CYP27B1 cause 1α-hydroxylase deficiency, also known as vitamin D-dependent rickets type I or hereditary pseudovitamin D-deficient rickets; very rare mutations in CYP2R1 can cause 25-hydroxylase deficiency. Both are characterized by low serum concentrations of 1,25(OH)2D, which respond to hormonal replacement with calcitriol. Mutations in CYP24A1 bring about a hypercalcemic syndrome caused by defective inactivation of 1,25(OH)2D. VDR mutations are the basis of hereditary vitamin D-resistant rickets (HVDRR), also known as vitamin D-dependent rickets type II, characterized by elevated serum 1,25(OH)2D concentrations and unresponsiveness to endogenous or exogenous 1,25(OH)2D. The disease may also be characterized by the presence of alopecia. Treatment of HVDRR often requires high doses of calcium administered either intravenously or orally to bypass the defect in VDR signaling.

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Erasmus MC: University Medical Center Rotterdam

Feldman, D., van der Eerden, B., Malloy, P.J. (Peter J.), & Miller, W.L. (Walter L.). (2017). Genetic Disorders Of Vitamin D Synthesis and Action. In Genetics of Bone Biology and Skeletal Disease: Second Edition (pp. 735–759). doi:10.1016/B978-0-12-804182-6.00039-3